Rituximab is a chimeric human/mouse IgG1 monoclonal antibody with human constant regions and variable murine regions derived from a murine anti-CD20 antibody (IDEC 2B8). Rituximab is directed toward CD20, a pan B-cell glycoprotein which is expressed on B lymphocytes from the pre-B-cell stage to the pre-plasma-cell stage. CD20 is a four-transmembrane glycoprotein that is involved in B-cell differentiation and activation, although its exact physiological function is not yet fully understood. Several characteristics make the CD20 antigen attractive for immunotherapy; since CD20 does not circulate in the plasma, it is neither internalized nor downregulated and there is no evidence that antibody binding leads to shedding from the cell sur face of the CD20+ target B cells. Among several mechanisms involved in B-cell killing by rituximab, its B-cell cytolytic activity mainly depends on antibody-dependent cell-mediated cytotoxicity (ADCC). Polymorphisms of the FcyRIII receptor which mediates ADCC seem to influence the response to rituximab. Other mechanisms such as complement-mediated lysis and induction of apoptosis may also contribute to the B-cell-depleting activity of rituximab. Interestingly, there is recent evidence suggesting that the mechanism of B-cell killing by rituximab depends on the tissue microenvironment (Fig. 8.4).
In vivo studies using hCD20 BAC (bacterial artificial chromosome) transgenic mice demonstrate that depletion of B lymphocytes varies among different B-cell compartments. In these mice, over 90% of the circulating B cells in the peripheral blood are depleted within minutes. In lymph nodes and the spleen, B-cell depletion occurs within 24 h after application of rituximab and within 7 days in the peritoneal cavity where significant B-cell depletion is delayed. Even though more than 90 % of follicular B cells in the spleen are depleted within 2 days after rituximab application, germinal center B cells, particularly marginal zone B cells, appear to be more resistant to killing. These differences in resistance to rituximab are neither due to lack of CD20 expression nor due to differences in drug bioavailability. Thus, the
Fig. 8.4. Mode of action of rituximab. B-cell killing is largely mediated by antibody-dependent cell mediated cytotoxicity (ADCC). Recent data indicates that the patient's FcyRIII allotype seems to influence the response to rituximab. In vitro studies have shown that rituximab effectively induces complement-dependent cytotoxicity (CDC) against B-cell lines and lymphoma cells. Induction of apoptosis may also contribute to B-cell killing
Fig. 8.4. Mode of action of rituximab. B-cell killing is largely mediated by antibody-dependent cell mediated cytotoxicity (ADCC). Recent data indicates that the patient's FcyRIII allotype seems to influence the response to rituximab. In vitro studies have shown that rituximab effectively induces complement-dependent cytotoxicity (CDC) against B-cell lines and lymphoma cells. Induction of apoptosis may also contribute to B-cell killing differences in kinetics and sensitivity to the B-cell cytolytic activity of rituximab seem to depend on protective microenvironmental factors. The expression of the CD20 antigen is not restricted to B cells. A small number of T cells and NK cells also express low levels of CD20. A recent study with 24 rheumatoid arthritis (RA) patients showed that these cell populations disappear for a mean of 5 months after rituximab therapy. The authors did not find significant changes in the total number or frequency of other T-cell subpopulations in the peripheral blood.
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